Arid1a restrains Kras-dependent changes in acinar cell identity

ELife
Geulah LivshitsScott W Lowe

Abstract

Mutations in members of the SWI/SNF chromatin remodeling family are common events in cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the mouse pancreas in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.

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Citations

Mar 21, 2019·Gut·Elisabeth Hessmann, Volker Ellenrieder
Jul 18, 2018·ELife·Zhe Zhang, Elisabeth Hessmann
Jun 20, 2020·Nature·Corina AmorScott W Lowe
Sep 17, 2020·Cancers·Carlotta Paoli, Alessandro Carrer
Feb 8, 2019·Laboratory Investigation; a Journal of Technical Methods and Pathology·Noboru IdenoBidyut Ghosh
Jun 27, 2019·Journal of Clinical Medicine·Yu-Hsuan HungMei-Ren Pan
Feb 5, 2021·Nature·Direna Alonso-CurbeloScott W Lowe
Mar 7, 2021·International Journal of Molecular Sciences·Yolanda Rodríguez GilVíctor Javier Sánchez-Arévalo Lobo
Jun 4, 2021·Cancer Discovery·Maria Paz Zafra, Lukas E Dow

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Datasets Mentioned

BETA
GSE114576
GSE114567

Methods Mentioned

BETA
RNAseq
RNA-seq
Assay
ChIP-seq
PCA
flow cytometry
genotyping
FACS
HTseq
PCR

Software Mentioned

Voom R /
bedtools
MACS2
STAR aligner
bowtie2
Bioconductor
HOMER
Axiovision
ATAC
HTseq

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